Nonsyndromic clefts of the lip and palate are a common congenital anomaly, occurring in about 1/800 live births. For CL plus/minus P, Orientals are at higher risk than Caucasians or Blacks; the need remains to test genetic hypotheses in Asian populations. To meet this need, we began a major collaborative effort in 1986 to study the genetics of cleft lip and cleft palate in Shanghai, China. Since 1986, we have ascertained more that 2,000 families through CL plus/minus P surgical probands; have collected demographic data between 1980 and 1989; and have collected developmental asymmetry data on the probands and their families. Genetic analyses of the 2,000 ascertained families yielded the striking result that a single autosomal recessive major locus was consistent with the data, leading us to propose this continuation of our research effort. The ultimate goal of this proposal is to characterize and map genetic loci for clefting. To this end, the specific aims of this continuation are: (1) to ascertain 100 multiplex clefting families containing about 1,000 individuals (in the 2,000 families ascertained, there are more than 250 multiplex families to chose from), obtain blood samples and extract DNA; (2) to perform cytogenetic studies in probands to search chromosomal rearrangements; (3) to type molecular markers on the families for target regions and loci, and also a genome-wide panel of markers; (4) to perform linkage analyses of clefting with each marker; (5) to assess the impact of heterogeneity; (6) to develop methods to incorporate significant effects of covariates (such as asymmetry and handedness) into analyses; (7) to explore the possibility of genomic imprinting in clefting. The answers to be gained from this study are essential to the effective genetic counseling of Oriental families as well as to prevention strategies in this racial group. In addition, this study will provide etiological clues for clefting in all races, and raise new hypotheses to be tested at a later date (e.g., and linkages detected would need to be confirmed in other populations, and eventually cloning of any implicated loci would be pursued).